title: An enhanced heterologous virus-like particle for human papillomavirus type 16 tumour immunotherapy.
abstract: Cervical cancer is caused by high-risk, cancer-causing human papillomaviruses (HPV) and is the second highest cause of cancer deaths in women globally. The majority of cervical cancers express well-characterized HPV oncogenes, which are potential targets for immunotherapeutic vaccination. Here we develop a rabbit haemorrhagic disease virus (RHDV) virus-like particle (VLP)-based vaccine designed for immunotherapy against HPV16 positive tumours. An RHDV-VLP, modified to contain the universal helper T cell epitope PADRE and decorated with an MHC I-restricted peptide (aa 48-57) from the HPV16 E6, was tested for its immunotherapeutic efficacy against the TC-1 HPV16 E6 and E7-expressing tumour in mice. The E6-RHDV-VLP-PADRE was administered therapeutically for the treatment of a pre-existing TC-1 tumour and was delivered with antibodies either to deplete regulatory T cells (anti-CD25) or to block T cell suppression mediated through CTLA-4. As a result, the tumour burden was reduced by around 50% and the median survival time of mice to the humane endpoint was almost doubled the compared to controls. The incorporation of PADRE into the RHDV-VLP was necessary for an E6-specific enhancement of the anti-tumour response and the co-administration of the immune modifying antibodies contributed to the overall efficacy of the immunotherapy. The E6-RHDV-VLP-PADRE shows immunotherapeutic efficacy, prolonging survival for HPV tumour-bearing mice. This was enhanced by the systemic administration of immune-modifying antibodies that are commercially available for use in humans. There is potential to further modify these particles for even greater efficacy in the path to development of an immunotherapeutic treatment for HPV precancerous and cancer stages.
authors.affiliation: Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
authors.forename: Khairunadwa
authors.initials: K
authors.lastname: Jemon
authors.forename: Vivienne
authors.initials: V
authors.lastname: Young
authors.forename: Michelle
authors.initials: M
authors.lastname: Wilson
authors.forename: Sara
authors.initials: S
authors.lastname: McKee
authors.forename: Vernon
authors.initials: V
authors.lastname: Ward
authors.forename: Margaret
authors.initials: M
authors.lastname: Baird
authors.forename: Sarah
authors.initials: S
authors.lastname: Young
authors.forename: Merilyn
authors.initials: M
authors.lastname: Hibma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D017929:Hemorrhagic Disease Virus, Rabbit / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009856:Oncogene Proteins, Viral / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000627:therapeutic use*; D012097:Repressor Proteins / Q000276:immunology; D047368:Tumor Burden; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D015678:Viral Structural Proteins / Q000378:metabolism; D014771:Virion / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; C584092:PC61 monoclonal antibody; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; D014614:Vaccines, Synthetic; D015678:Viral Structural Proteins; C081149:viral protein 60, rabbit hemorrhagic disease virus